Abstract Ionizing radiation (IR) exposure has deleterious effects on multiple organ systems and can be lethal both acutely and later due to the delayed effects. In the event of a deliberate radiation attack or accidental exposure to radiation, a countermeasure can be used to treat exposed populations and prevent death and disability. No agent has been approved by the FDA to treat the delayed effects of acute radiation exposure (DEARE) and our project will address that unmet medical need. IPW-5371 has the properties of an ideal radiation countermeasure: chemically stable at room temperature; orally bio-available; efficacy with once-a-day dosing; targeting a mechanism of action that has been safely inhibited in human clinical trials. The results from the experiments in this proposal will advance the development of IPW-5371 to protect the organs in the case of an unexpected exposure to radiation. We have previously demonstrated that the Innovation Pathways? small molecule TGF? inhibitor, IPW-5371, is effective against DEARE in a thoracic radiation mouse model as measured by improved survival and cardiopulmonary function, when dosed 24 hours post IR. In this proposal, we will establish that IPW-5371 is effective in treating multi- organ DEARE to the heart, lung, kidney and intestine, in a mouse radiation model as a single agent or in combination with G-CSF. Specific Aim 1a: Demonstrate that IPW-5371, as a single agent, can extend survival of C57BL/6 mice exposed to TBI (8.5 Gy) when drug dosing (30mpk/day in chow) is initiated 24 hours post-TBI and continued for 21 months. Specific aim 1b: Demonstrate that IPW-5371, as a single agent can improve secondary endpoints including: decrease fibrosis; protect function; and block TGF? signaling in multiple organs of C57BL/6 mice when measured at 4, 9, and 21 months post TBI, following an established mouse model. Specific Aim 2: Establish that IPW-5371 + G-CSF (IPW-5371: 30 mpk per day in chow for 21 months and the G-CSF will be injected for two weeks dosing initiated 24 hours post TBI, 8.5 Gy) can protect against heart, lung, intestine and kidney DEARE (as described in Specific aim 1b) and protect against the early, lethal effects of H-ARS as measured by survival at 30 days verses TBI, untreated mice. There will be a total of 400 mice divided into eight groups. Groups A-D are the un- irradiated controls with Grp A receiving vehicle (SC saline injection for 16 days) Grp B receiving G-CSF, and Grp C receiving IPW-5371, and Grp D receiving IPW-5371+G-CSF. All animals receive drug(s) or vehicle starting 24 hours post TBI. IPW-5371 (administered in chow, 30mpk/day/mouse) for 21 months and G-CSF is administered daily for 16 days (SC, 125 ?g/kg (2.5 ?g/mouse, qd). Groups E-H receive TBI, 8.5 Gy. Mice to be exposed to uniform TBI at a dose rate of 1.00 Gy per minute. Grp E receives vehicle, Grp F receives G-CSF and Grp G receives IPW-5371 and Grp H receives IPW-5371+G-CSF.